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Phase 2 Trial of Regorafenib in Recurrent/Metastatic Adenoid Cystic Carcinoma
Antoine Desilets1, Joris L Vos2, Nora Katabi3
1Head and Neck Medical Oncology Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York.
Purpose:
There is a significant need for effective therapies to treat recurrent/metastatic (R/M) adenoid cystic carcinoma (ACC). This study evaluated the multitargeted VEGFR tyrosine kinase inhibitor (TKI) regorafenib in patients with R/M ACC.
Patients And Methods:
Patients with progressive R/M ACC were treated with regorafenib until disease progression, consent withdrawal, or excessive toxicity. The co-primary endpoints were best overall response and 6-month progression-free survival (PFS). Genomic and transcriptomic biomarker analyses were performed in tumors from trial participants.
Results:
Thirty-eight patients were enrolled, including 7 (18%) patients with prior VEGFR TKIs. No objective responses were observed. The 6-month PFS was 45%, and the median PFS was 7.2 months (95% confidence interval, 5.2-11.9 months). The presence of either activating NOTCH1 (22%) or KDM6A alterations (24%) was associated with decreased PFS [HR 2.6; 95% confidence interval (CI), 1.1-6.1; P = 0.03]. Bulk RNA sequencing of pretreatment tumors revealed that regorafenib clinical benefit (CB; PFS ≥ 6 months; n = 11) was associated with the native enrichment of immune-related signatures. Immune deconvolution revealed a greater degree of macrophage and T-cell infiltration in CB tumors. Tumors from patients with no clinical benefit (NCB; PFS < 6 months; n = 9) had greater expression of signatures related to cell-cycle progression (E2F targets, G2-M checkpoint).
Conclusions:
The trial failed to meet the prespecified 6-month PFS and best overall response targets. We hypothesize that TKI efficacy may be reliant upon an interplay between kinase inhibition and the ACC immune microenvironment, whereas programs promoting cell-cycle progression may contribute to TKI resistance. These observations suggest that trials evaluating CDK4/6 inhibition plus a VEGFR TKI should be considered.
Insights
Regorafenib did not meet primary endpoints for recurrent/metastatic adenoid cystic carcinoma (ACC). Clinical benefit was linked to immune signatures, while cell-cycle progression correlated with resistance, suggesting combination therapies.
Area of Science:
- Oncology
- Translational Research
- Cancer Genomics
Background:
- Adenoid cystic carcinoma (ACC) is a rare cancer with limited treatment options for recurrent/metastatic (R/M) disease.
- Targeted therapies, such as tyrosine kinase inhibitors (TKIs), are being investigated for R/M ACC.
Purpose of the Study:
- To evaluate the efficacy of regorafenib, a multitargeted VEGFR TKI, in patients with R/M ACC.
- To identify potential genomic and transcriptomic biomarkers associated with response to regorafenib.
Main Methods:
- A phase II clinical trial treated patients with progressive R/M ACC with regorafenib.
- Co-primary endpoints included best overall response and 6-month progression-free survival (PFS).
- Tumor samples underwent genomic and transcriptomic analyses to identify biomarkers.
Main Results:
- No objective responses were observed; 6-month PFS was 45% (median PFS 7.2 months).
- Activating NOTCH1 or KDM6A alterations were associated with decreased PFS.
- Clinical benefit (PFS ≥ 6 months) correlated with immune-related signatures and increased macrophage/T-cell infiltration.
- No clinical benefit (PFS < 6 months) was linked to cell-cycle progression signatures.
Conclusions:
- Regorafenib did not meet the predefined efficacy targets for R/M ACC.
- TKI efficacy may depend on the interplay between kinase inhibition and the tumor immune microenvironment.
- Cell-cycle progression pathways may confer resistance to TKIs, suggesting potential for combination therapies (e.g., CDK4/6 inhibitors plus VEGFR TKIs).
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